Safety and efficacy of direct oral anticoagulants in comparison to warfarin in obese patients with atrial fibrillation: A systematic review and meta‐analysis

Abstract Background and Aim Obesity affects nearly 650 million adults worldwide, and the prevalence is steadily rising. This condition has significant adverse effects on cardiovascular health, increasing the risk of hypertension, coronary artery disease, heart failure, and atrial fibrillation (AF). While anticoagulation for obese patients with AF is a well‐established therapy for the prevention of thromboembolism, the safety and efficacy of different anticoagulants in this specific population are not well explored. This meta‐analysis aimed to compare direct oral anticoagulants (DOAC) to vitamin K antagonists in obese populations with AF. Methods The PRISMA guidelines were followed for this meta‐analysis, registered in PROSPERO (CRD42023392711). PubMed, PubMed Central, Embase, Cochrane Library, and Scopus databases were searched for relevant articles from inception through January 2023. Two independent authors screened titles and abstracts, followed by a full‐text review in Covidence. Data were extracted in Microsoft Excel and analyzed using RevMan v5.4 using odds ratio as an effect measure. Results Two thousand two hundred fifty‐nine studies were identified from the database search, and 18 were included in the analysis. There were statistically significant reductions in the odds of ischemic and hemorrhagic stroke in the DOAC group compared with the VKA group (OR 0.70, CI 0.66–0.75) and (OR 0.47, CI 0.35–0.62), respectively. In addition, the DOAC group exhibited lower odds of systemic embolism (OR 0.67, CI 0.54–0.83), major bleeding (OR 0.62, CI 0.54–0.72), and composite outcome (OR 0.72, CI 0.63–0.81). Conclusion Based on the findings from this meta‐analysis, DOACs demonstrate superior safety and efficacy in obese patients with AF compared with VKAs. These results may have significant implications for guiding anticoagulation strategies in this patient population.

and ESC (2020) recommended the benefits of DOACs over VKAs in OAC-eligible AF patients.Still, they have not commented on the use of DOAC in AF patients with obesity, except AHA/ACC/HRS's recommendation of DOAC use among class III obesity patients with AF. 9,10 Obesity affects the pharmacokinetics of drugs by altering their volume of distribution (V d ), peak concentration (C max ), and drug exposure (area under curve, AUC), as well as drug clearance. 11Thus, obesity also affected the pharmacokinetics and pharmacodynamics of DOACs among obese patients. 12Due to concern about subanticoagulation with the use of fixed-dose regimen, International Society on Thrombosis and Hemostasis (ISTH) (2016) recommended standard DOAC dosing for patients with a BMI ≤ 40 kg/m 2 and weight ≤ 120 kg for prevention of ischemic stroke and systemic arterial embolism in nonvalvular AF while cautioning against DOAC use in patients with a BMI > 40 kg/m 2 or weight > 120 kg due to limited data and potential pharmacokinetics or pharmacodynamic concerns.If DOACs need to be used in such patients, they are recommended to consider monitoring drug-specific levels and, if below the expected range, consider switching to a VKA rather than adjusting the DOAC dose. 13Zhao et al. pointed out that obesity may have a modest effect on the pharmacokinetics of dabigatran, apixaban, rivaroxaban, or edoxaban.They highlighted that the standard doses of apixaban, rivaroxaban, and edoxaban are effective and safe in morbidly obese patients with AF.At the same time, the body weight is inversely affected by the peak concentration of dabigatran, with a significantly increased risk of gastrointestinal bleeding. 12There are now a growing number of studies studying the effectiveness and safety of the DOAC among obese or morbidly obese patients with AF, showing that they have better outcomes compared with those with normal BMI, and it's being depicted as an "obesity paradox." 14rlier meta-analyses on the use of DOAC compared with warfarin in morbidly obese patients with AF showed mixed results. 15,16However, these studies were unable to fully appraise the efficacy and safety of the DOAC compared with warfarin among obese as well as morbidly obese patients with AF.Therefore, this systematic review and meta-analysis aimed to investigate the comparative safety and efficacy of DOACs compared with VKAs in obese patients with AF, defining safety as freedom from any major bleeding event and efficacy as freedom from stroke or systemic thromboembolism.

| Protocol
The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed for this systematic review and meta-analysis.The protocol is registered in PROSPERO 2023 CRD42023392711.The PRISMA checklist is included in a supplementary file (Supplementary material).

| Search strategy
PubMed, PubMed Central, Embase, Cochrane Library, and Scopus databases were searched in January 2023.An appropriate combination of search words such as "atrial fibrillation," "direct oral anticoagulant," "DOAC," "vitamin K antagonist," "Warfarin," "obesity" and applicable Boolean operators were used.The search method will be described in detail in a supplemental file.

| Eligibility criteria
This meta-analysis contained prospective and retrospective studies in which obese patients with nonvalvular AF received either DOAC or Warfarin and included case-control, cohort, and randomized control trials (RCTs).Conference abstracts, editorials, comments, qualitative and viewpoint articles, case reports, review articles, and other metaanalyses were excluded.

| Outcomes measured
The primary efficacy outcome was a composite of stroke, systemic embolism, myocardial infarction (MI), or any cause of death.The secondary outcomes were ischemic stroke, systemic embolism, and all-cause mortality.The primary safety outcome was major bleeding.
We also analyzed the outcome of all-cause mortality.

| Study selection
Two independent reviewers screened the titles and abstracts using Covidence, while a third reviewer resolved conflicts.Two reviewers completed the full-text review, and conflicts were resolved by another reviewer among the list of authors.Data was then extracted for qualitative and quantitative processing.

| Data extraction
A standardized form was designed in Microsoft Excel to extract pertinent data, including study authors, study details, quality, and endpoints.The endpoints of this meta-analysis were all-cause mortality, ischemic stroke, systemic embolism, a composite of ischemic stroke and systemic embolism, and a major bleeding event.

| Study quality
The quality of individual articles was assessed using the Joanna Briggs Institute's critical appraisal (JBI) tools for the risk of bias 17 (Supporting Information: Table 1).ROB-2 tool used for risk of bias assessment of RCTs 18 (Supporting Information: eFigure 1).
Two authors independently assessed each study design and the number of patients with each outcome.A third person then resolved conflicts.

| Data analysis
Data was analyzed using RevMan v5.4. 19An odds ratio (OR) was used for outcomes such as mortality, ischemic stroke, systemic embolism, composite of ischemic stroke and systemic embolism, and a major bleeding event.
Heterogeneity was measured by the I 2 test among the included studies.A random effect model was used for analysis to consider heterogeneity.
Sensitivity analysis was performed based on the type of DOAC used and BMI class to test the robustness of the analysis.

| RESULTS
Among 2259 studies identified from the database search, 2085 were screened for title and abstract after removing 174 duplicates.After excluding 2009 studies during title and abstract screening, full text of 76 studies were assessed for eligibility.Fifty-eight studies were excluded from the full-text review, and 18 were included in the analysis.Among the 18 studies included, 16 were retrospective cohort studies, and 2 were randomized controlled trials.The PRISMA flow diagram for the review is shown in Figure 1.
F I G U R E 1 PRISMA 2020 flow diagram for the systematic review.
T A B L E 1 Baseline characteristics of studies and participants, including their comorbidities.2).In the subanalysis comparing the specific  4).In the subanalysis comparing different DOAC agents with the warfarin group, there were no significant difference occurrence of systemic embolic events for three DOAC agents: rivaroxaban, apixaban, and dabigatran (Supporting Information: eFigure 4).

| Major bleeding
Eighteen studies reported major bleeding events with an incidence rate of 3

| Subanalysis based on BMI classes
Subanalysis of the clinical efficacy and safety of DOAC agents compared with warfarin use was performed based on the obesity classification: obesity class I (30-34.9kg/m 2 ), obesity class II (35-39.9kg/m 2 ), and obesity class III (>40.0 kg/m 2 ).We found that the use of DOACs was associated with statistically significant reductions in the composite outcome of ischemic stroke, systemic embolism, and major bleeding across all three obesity classes.
However, the individual outcomes of systemic embolism in obesity classes I and III and the major bleeding in obesity classes I and II were not significant.

| Composite outcome
In the subanalysis across different obesity classes, there was a significantly lower occurrence of the composite outcomes in all three obesity classes: obesity class I (OR 0.74, 95% CI 0.62-0.90),obesity class II (OR 0.76, 95% CI 0.59-0.97)and obesity class III (OR 0.72, 95% CI 0.60-0.87) in comparison to the warfarin group (Supporting Information: eFigure 11).

| Publication bias
Publication bias for the composite outcome, stroke, major bleeding, and all-cause mortality was checked with a Funnel plot, which showed the asymmetric distribution of studies signifying significant publication bias (Supporting Information: eFigure 15).

| DISCUSSION
Obesity is a well-established risk factor for AF, which itself carries a high risk of major life-threatening thromboembolism and ischemic stroke. 38Thus, primary as well as secondary prevention of the thromboembolism and ischemic stroke risk with anticoagulation is one of the cornerstones of AF management in suitable AF patients. 39e to the better clinical efficacy profile (systemic embolism and the stroke) as well as the clinical safety (major bleeding and intracranial Our meta-analysis revealed that obese patients with AF who received DOACs, as compared with VKAs, had significantly lower occurrences of composite events as well as individual events: stroke (ischemic as well as hemorrhagic) and systemic embolic events, in overall.The DOACs also significantly lowered major bleeding rates, including GI bleeding, ICH, and all-cause mortality in this patient cohort.Among different DOAC agents, rivaroxaban and apixaban use had significantly lower occurrence of composite events, ischemic as well as hemorrhagic strokes, major bleeding including GI bleeding as well as ICH, and all-cause mortality compared with warfarin use.
Dabigatran use had a significantly lower occurrence of composite events, GI bleeding, and ICH than warfarin use.Across all three classes of obesity, the DOAC had significantly lower occurrences of composite events as well as ischemic stroke events.Whereas only class II obesity and class III obesity had a significantly lower occurrence of systemic embolism events and major bleeding, respectively, when using DOACs compared with warfarin.None of the DOAC agents were associated with a significant reduction of systemic embolic events on individual comparison with warfarin use.embolism, along with a reduction in major bleeding, with rivaroxaban in comparison to warfarin use in obese patients with AF. 40 In this study, there were no significant reductions in stroke and systemic embolism, and major bleeding events across different BMI classes.In contrast, in our study, there was a statistically significant reduction in pared with the warfarin group; however, the dabigatran group had similar rates of stroke and systemic embolism as the warfarin group, while all three DOACs were associated with lower major bleeding rates than warfarin. 26These findings contrast with our subanalysis, which showed that compared with warfarin, apixaban, rivaroxaban, and dabigatran all have significantly lower stroke rates; however, major bleeding rates were only significantly lower in apixaban and rivaroxaban groups.One potential explanation for the discrepancy in outcomes could be the mechanism of action of DOACs, as dabigatran is a factor IIa inhibitor while apixaban and rivaroxaban are factor Xa inhibitors. 41The pharmacokinetics of dabigatran also differ from apixaban and rivaroxaban since dabigatran undergoes hepatic glucuronidation, while apixaban and rivaroxaban are metabolized through the cytochrome P450 system. 41retrospective study by Briasoulis et al. interestingly reported that in patients weighing over 120 kg, apixaban had a higher risk of stroke than warfarin, while rivaroxaban and dabigatran had a similar risk as warfarin, and all three DOACs had a lower bleeding risk.24 This differs from the results of our study and may be partially explained by the diversity in comorbidity burden among the various DOACs and the differences in the patient population.42 Our results do have some limitations.First, we did not make a comparison of obese to nonobese or underweight populations.
Second, the data set did not include INR levels in patients on F I G U R E 4 Forest plot showing significantly lower occurrence of systemic embolic events in the DOAC group compared with the Warfarin group using the random effect model.
F I G U R E 5 Forest plot showing significantly lower occurrence of major bleeding events in the DOAC group compared with VKA group using random effect model.
warfarin, and it's possible that subtherapeutic or supratherapeutic warfarin effects could influence the rates of stroke and bleeding.
Despite these limitations, the meta-analysis has multiple strengths, including a large number of studies and a large patient population, increasing the power of the results.The analysis also compared different individual DOACs to warfarin and allowed subanalysis of various obesity classes.
DOACs appear to show superior safety and efficacy (stroke, systemic embolism, MI, bleeding, or death) when compared with VKAs (warfarin) in obese populations with AF.As the totality of this evidence mostly came from observational studies, additional data from larger randomized controlled trials will be required to discern the appropriate DOACs, dosage regimens, and BMI extremes.
hemorrhage), thus higher mortality benefit, of DOACs over the warfarin, DOACs are recommended over warfarin for the anticoagulation in AF patients in the 2023 ACC/AHA/ACCP/HRS guideline.However, there was little clinical evidence to support this clinical safety and efficacy superiority profiles of DOACs over warfarin among obese patients with AF.So, 2023 ACC/AHA/ACCP/HRS guideline recommends DOAC among AF patients with class III obesity (class of recommendation 2a and the level of evidence B-NR) only while no comments regarding which type of anticoagulants is suitable for AF patients with class I or II obesity. 10Therefore, it is imperative to investigate the safety and efficacy of anticoagulation in AF patients with obesity.This comprehensive systematic review and meta-analysis evaluated the efficacy and safety of DOACs, as compared with VKAs, within the obese patient population suffering from nonvalvular AF.
both systemic embolism and major bleeding across obesity classes in DOAC group, except the systemic embolism in obesity classes I and III, and the major bleeding in obesity classes I and II, where reduction was not statistically significant.These disparities in our findings and by Costa et al. among different BMI classes seem to be F I G U R E 2 Forest plots show a significantly lower occurrence of composite events in the DOAC group than in the Warfarin group using the random effect model.F I G U R E 3 Forest plot showing significantly lower occurrence of stroke events in the DOAC group compared with Warfarin group using random effect model.due to the type of DOACs used, differences in the number of patients in different BMI classes, and differences in the statistical analysis used.The post-hoc analysis of the ARISTOTLE trial based on the obesity performed by Deitelzweig et al. showed a lower risk of stroke and systemic embolism in apixaban and rivaroxaban groups com-

Table 2 .
baseline medications, and clinical outcomes were collected and analyzed, as presented in Tables1 and 2and Supporting Information: Clinical efficacy and safety outcomes among the included participants.